Helicobacter pylori is a spiral-shaped, Gram-negative, microaerophilic bacterium found in the stomach and upper gastrointestinal tract of perhaps more than half of the world's population. Many with this infection are asymptomatic, yet Helicobacter pylori can cause chronic gastritis in children and adults, and is associated with an increased risk of developing gastric cancer and mucosal-associated-lymphoid-type (MALT) lymphoma. Unbeknownst to the medical community for many years, this bacterium was responsible for most cases of duodenal and peptic ulcers. These ulcers are associated with pain, indigestion, nausea, and loss of appetite. Bleeding from these ulcers could cause fatigue from anemia, and blood may show up in the vomit and stool. Before this bacterium was discovered, gastric and intestinal ulcers were thought to be caused mainly by spicy foods, stress, and excessive stomach acid secretion. Patients were given long-term medications, such as histamine H2-receptor antagonists (H2-blockers) and proton pump inhibitors, without a chance for permanent cure. Although these medications relieve ulcer-related symptoms, heal gastric mucosal inflammation, and may heal the ulcer, H2-blockers and proton pump inhibitors do not treat the infection and ulcers often reoccur, especially when acid suppression is removed. Only antibiotics have the potential to cure a Helicobacter pylori infection and prevent ulcer reoccurrence. It is believed that once this bacterium is eliminated, so is the chronic inflammation in the walls of the stomach and intestine that make these tissues more vulnerable to damage caused by digestive juices. Importantly, it was found that higher levels of acid suppression achieved with a proton pump inhibitor could potentiate the activity of antibiotics used to eradicate Helicobacter pylori infection. Modern regimens of eradicating Helicobacter pylori infection therefore include a proton pump inhibitor and antibiotics.
Proton pump inhibitors suppress stomach acid secretion by inhibiting or irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system of the gastric parietal cells to prevent the secretion of hydrogen ions. This mechanism of action is different from that of H2-blockers, which block the action of histamine on the histamine H2-receptors of parietal cells to decrease their production of acid. The proton pump inhibitor is often provided as a tablet or capsule, often containing delayed release, enteric-coated granules that survive the low pH of the stomach, and release at higher pH in the intestines, as proton pump inhibitors are acid labile. In the more neutral condition of the small intestines, the proton pump inhibitor is rapidly absorbed into the bloodstream. The strength of the proton pump inhibitor usually ranges from 10 mg to 60 mg, and is often taken 1 to 2 times per day. Lansoprazole and omeprazole are the most commonly prescribed proton pump inhibitors, although other proton pump inhibitors include aripiprazole, dexlansoprazole, esomeprazole, pantoprazole, and rabeprazole. While many proton pump inhibitors are benzimidazole derivatives, newer proton pump inhibitors include imidazopyridine derivatives. Proton pump inhibitors, such as lansoprazole, often have inter-individual and intra-individual differences in pharmacokinetic profiles and can be affected by differences in cytochrome P450 enzyme genotypes; polymorphisms including those of CYP2C19 and CYP3A.
Antibiotics are given concomitantly with the proton pump inhibitor during Helicobacter pylori eradication therapy. At least two different antibiotics are recommended as part of Helicobacter pylori eradication therapy to reduce the risk of treatment failure and antibiotic resistance. The most commonly prescribed Helicobacter pylori triple therapy includes amoxicillin, clarithromycin, and either lansoprazole or omeprazole, each as a separate, individual tablet or capsule. Amoxicillin is a broad antimicrobial beta-lactam that inhibits the synthesis of the bacterial cell wall in replicating bacteria. Amoxicillin is bactericidal for both gram-positive and gram-negative bacteria and is destroyed by beta-lactamase produced from both types of bacteria. Clarithromycin is an advanced-generation macrolide antibiotic with a broad in vitro antimicrobial spectrum. It interferes with protein synthesis in bacteria. Clarithromycin is rapidly and nearly completely absorbed from the gastrointestinal tract and has extensive diffusion in the tissues and bodily fluids. It forms a microbiologically active primary metabolite, 14-(R)-hydroxyclarithromycin, primarily by the cytochrome, CYP3A.
If a patient is believed to be resistant to clarithromycin, an alternative antibiotic may be prescribed, such as tetracycline. Tetracycline is another broad-spectrum polyketide antibiotic that inhibits protein synthesis in bacteria. Metronidazole is a nitroimidazole antibiotic that inhibits nucleic acid synthesis primarily in anaerobic bacteria. However, metronidazole is less used, perhaps because it appears to be somewhat mutagenic and carcinogenic.
The Helicobacter pylori triple therapy regimen generally lasts for 7 to 14 days, and is preferably 10 or 14 days. It is very common for a physician to prescribe 500 mg amoxicillin capsules, 500 mg clarithromycin tablets, and 30 mg lansoprazole or 20 mg omeprazole delayed-release capsules as a triple therapy. These regimens include taking two amoxicillin 500 mg capsules, one 500 mg clarithromycin tablet, and one 30 mg lansoprazole or 20 mg omeprazole delayed-release capsule, administered together twice daily (in the morning and evening) for 10 or 14 days. These therapies therefore comprise eight pills per day, four in the morning and four in the evening. These pills come from 3 different prescription bottles. To provide greater convenience to physicians and patients, convenience kits, daily blister cards containing morning and night doses of these pills, have been produced. Still, these convenience kits contain 3 different pills of active ingredients, and there is some risk of accidentally taking one or more pills from the evening dose when taking pills from the morning dose, and vice versa. Moreover, the taking of 8 pills per day (112 pills over 2 weeks) for the triple therapy, not to mention if the patient is taking other medications, is a great number of pills that can lead to poor patient compliance or distress. Some patients have a gag reflex and have trouble swallowing pills.
There exists a great need for an improved Helicobacter pylori eradication therapy that solves the problems inherent in prior Helicobacter pylori eradication therapies; namely poor compliance, patient distress and confusion among a great number of different pills, which may also lead to medication dosing errors and increased side effects. The present invention fulfills this need by providing at least one proton pump inhibitor active pharmaceutical ingredient, and at least two different antibiotic active pharmaceutical ingredients, in the same solid oral dosage form. The present invention provides the advantage of greatly reducing the number of pills administered in a Helicobacter pylori eradication regimen. Preferably, only 1 to 3 of these pills are taken in the morning and evening, for a preferable total of 2 to 6 pills taken per day, thus greatly improving patient compliance in a regimen lasting up to 14 days. Since each of these pills are identical, a single bottle can contain them to avoid confusion and medication errors. The present invention also provides new formulations and methods of improving stability of these active pharmaceutical ingredients, thereby assuring the identity, strength, quality, purity, potency, and safety of the solid dose drug product of the invention. At least one antibiotic active pharmaceutical ingredient is encapsulated independently from at least one other antibiotic active pharmaceutical ingredient within the same solid oral dosage form. The present invention improves the standard of patient care in Helicobacter pylori eradication therapy and provides therapies ideally suited for the different metabolic needs of patients.